SENSORY ATAXIA AND MUSCLE-SPINDLE AGENESIS IN MICE LACKING THE TRANSCRIPTION FACTOR EGR3

Muscle spindles are skeletal muscle sensory organs that provide axial and limb position information (proprioception) to the central nervous system. Spindles consist of encapsulated muscle fibers (intrafusal fib ers) that are innervated by specialized motor and sensory axons. Altho ugh the molecular mechanisms involved in spindle ontogeny are poorly u nderstood, the innervation of a subset of developing myotubes (type I) by peripheral sensory afferents (group la) is a critical event for in ducing intrafusal fiber differentiation and subsequent spindle formati on(1-3) The Egr family of zinc-finger transcription factors, whose mem bers include Egr1 (NGFI-A), Egr2 (Krox-20), Egr3 and Egr4 (NGFI-C), ar e thought to regulate critical genetic programs involved in cellular g rowth and differentiation (refs 4-8, and W.G.T. et al., manuscript sub mitted). Mice deficient in Egr3 were generated by gene targeting and h ad gait ataxia, increased frequency of perinatal mortality, scoliosis, resting tremors and ptosis. Although extrafusal skeletal muscle fiber s appeared normal, Egr3-deficient animals lacked muscle spindles, a fi nding that is consistent with their profound gait ataxia. Egr3 was hig hly expressed in developing muscle spindles, but not in la afferent ne urons or their terminals during developmental periods that coincided w ith the induction of spindle morphogenesis by sensory afferent axons. These results indicate that type I myotubes are dependent upon Egr3-me diated transcription for proper spindle development.